There is evidence that low-energy infrared laser irradiation (LELI) can modify a number of disease states, and in preclinical and clinical studies we have developed preliminary data showing that stroke is among them. Since intravenous tissue plasminogen activator (tPA) is currently the only FDA-approved treatment for acute stroke, but increases the absolute rates of resolution of symptoms only from 25% to 38%, there is need for additional therapeutic modalities to further contain or eliminate brain damage. We have developed a series of animal cerebral ischemia and hemorrhage models that, when used in a coordinated fashion, should help identify many of the important variables in LELI that pertain to its viability, safety, and efficacy as an adjunctive therapy to thrombolysis. Toward this end, this project is designed to achieve the following specific aims: (1) Examine the interaction of LELI with tPA therapy using a rabbit small clot brain embolism model (SCEM), which allows monitoring of a behavioral endpoint. This approach should yield information that helps to predict the clinical outcome of LELI combined with tPA in humans. The study also examines whether there is any effect of LELI on tPA-induced intracerebral hemorrhaging in the large clot embolism model (LCEM), which will serve to warn or reassure clinical investigators about the potential of LELI side effects in stroke victims. (2) Conduct a phase II clinical trial to test safety and preliminarily assess efficacy of LELI in combination with tPA with acute stroke patients. One approach to stroke therapy, in addition to thrombolysis, is to provide some form of neuroprotection immediately after stroke onset to reduce the damage caused by lack of blood flow and increase the window of opportunity for thrombolytic therapy. A second strategy is to administer neuroprotection after initiation of thrombolysis to reduce damage while thrombolysis is occurring. A third is to induce neuroprotection after thrombolysis is complete to salvage tissue that would otherwise die even though blood flow has been restored. Finally, it would be useful to develop strategies to produce recovery of function that may restore at least some neurological function. LELI is potentially capable of producing all of these effects. The potential impact of the study results on acute stroke therapeutics is thus far-reaching.